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Polyesters are an attractive class of polymer that can be readily modified with a wide range of different comonomers, during polymerization or with melt blending, to achieve a wide variety of physical properties. This research primarily focuses on polyesters that incorporate rigid aromatic structures that have excellent potential to enhance thermal and mechanical properties. Copolyesters were prepared through melt polycondensation of diesters and diols in the presence of an exchange catalyst. Monomer incorporation was verified with nuclear magnetic resonance (NMR) and molecular weights were obtained by measuring inherent viscosity (ninh). Physical properties were assessed with thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and rheology. Mechanical properties were assessed with tensile and impact testing. Copolyesters of poly(ethylene terephthalate) (PET) were synthesized by substituting dimethyl terephthalate (DMT) with dimethyl 4,4'-biphenyldicarboxylate (4,4'BB) resulting in enhanced glass transition (Tg) temperatures relative to PET while affording melting temperatures (Tm) low enough to allow facile melt processing. Further modification with dimethyl isophthalate (DMI) or dimethyl 3,4'-biphenyldicarboxylate (3,4'BB) slowed crystallization sufficiently to allow biaxial orientation, leading to further studies assessing the permeability of oriented films. Novel amorphous polyesters were synthesized with 3,4'BB or 4,4'BB in combination with neopentyl glycol (NPG), 1,4-cyclohexandimethanol (CHDM) and ethylene glycol (EG). Use of multiple diols produced clear, amorphous copolyesters with Tgs as high at 129 C. A series of novel high temperature(Tm) copolyesters were synthesized from dimethyl 2,6-naphthalenedicarboxylate (DMN) and 4,4'BB combined with CHDM. Studies were performed with standard DSC and thin film calorimetry to show the convergence of multiples melting endotherms in an effort to determine their origin. Preliminary work was performed on the modification of poly(1,4-cyclohexylenedimethylene terephthalate) (PCT), poly(1,4-cyclohexylenedimethylene 2,6-naphthalate) (PCN) and poly(1,4-cyclohexylenedimethylene 4,4'-bibenzoate) (PCB) with dimethyl p-terphenyl-4,4''-dicarboxylate. / PHD / Polyesters have a unique balance of properties that sets them apart from other polymers formed by step growth reactions. The transesterification reaction that forms polyesters occurs continually at reaction temperatures, making it easy to randomly distribute a mixture of different comonomers along the backbone during the polymerization process, or even when blending two different polyesters. Poly(ethylene terephthalate), commonly referred to as PET, is the most important polyester currently in production, and is prized for its transparency, chemical resistance, and recyclability. PET was first made by John Whinfield and James Dickson at Calico Printers’ Association of Mansfield, in 1941 and was eventually licensed to DuPont in the 1970s. It has since become a valuable resource for producing synthetic textiles and replacing heavier materials, such as glass and metal, to produce lightweight containers, especially for food storage. Many of the polyesters, such as PET, that we see on a daily basis are actually copolyesters that contain low levels of additional comonomers that have been added to improve some property of the final polymer or to facilitate processing. In research, modification of polyesters with different comonomers broadens our understanding in how the molecular structure of comonomers affects polyester properties. This makes it possible to tune a copolyester’s physical properties in a way that can enhance its suitability for a wide range of applications. The research described in this dissertation is focused on exploring how rigid monomer structures containing multiple aromatic rings might be used to produce polyesters with improved performance relative to current commercial polyesters. Materials that demonstrate good barrier to gases such as CO₂ and O₂ are important for packaging that can seal in and preserve food and beverages. In our research, we modified PET with bibenzoate structures to produce films that showed improved gas barrier when stretched in a manner that imitates the stretch blow molding process used to produce bottles. These materials showed good promise for packaging capable of preserving food for longer periods of time. Clear, food safe plastics that do not deform at the boiling temperature of water are important for baby bottles and durable dishwasher safe containers, which are commonly sterilized with boiling water. Until recently, such materials were produced from bisphenol-A polycarbonate (BPA PC), which fell out of favor for food safe applications over concerns that BPA, believed to have endocrine disrupting activity, may leach into food and beverages. Bibenzoate monomers, which increases the application temperature of many polyesters, were combined with different combinations of diol monomers to produce transparent copolyesters that are usable at higher temperatures. These materials demonstrated excellent potential as food safe alternatives to BPA containing materials. Crystalline plastics that resist distorting at high temperatures are important for applications in the electronics and automotive industry. Semicrystalline polyesters provide less expensive alternatives to the costly liquid crystalline polymers commonly used for high temperature applications. We explored the properties of a number of semicrystalline copolyester compositions capable of exceeding the application temperature of semicrystalline polyesters currently on the market.

Nombre de principes actifs rencontrent des problèmes liés à leur faible hydrosolubilité : mauvaise biodisponibilité, métabolisation désactivante, effets secondaires. Pour contourner ce problème, des polyélectrolytes amphiphiles aléatoires ont déjà été étudiés. S'ils ont amélioré la solubilité apparente de composés hydrophobes, ils étaient parallèlement toxiques ou non dégradables, donc non éliminables par l'organisme. Dans ce mémoire, nous présentons la synthèse de différentes malolactones substituées. La copolymérisation anionique par ouverture de cycle de ces lactones a permis d'obtenir une famille de polyanions amphiphiles aléatoires avec un taux d'hydrophobisation variable et contrôlé, et des chaînes latérales, aliphatiques ou aromatique, de différentes longueurs. Ces polymères augmentent la solubilité aqueuse apparente de composés hydrophobes. Lorsque le composé est cationique, une synergie entre interactions hydrophobes et électrostatiques a été mise en évidence. La solubilité apparente de molécules anti-infectieuses a ainsi pu être améliorée de plusieurs ordres de grandeur. Dans les conditions d'une administration intraveineuse (NaCl 9 g.L-1 et pH = 7,5), ces polymères forment préférentiellement des micelles intramoléculaires qui ne sont pas sensibles aux effets de dilution. Un tel système de transport de principes actifs ne produirait donc aucune libération prématurée. Ces polymères étant de plus dégradables, ils pourraient libérer le principe actif et seraient éliminables par l'organisme. Les polymères présentés dans ce manuscrit remplissent les principaux critères physico-chimiques pour former un système de transport de molécules actives. / Lots of drugs meet some problems because of their poor water-solubility : poor bioavailability, desactivating metabolization, side effects. To overcome these problems, some amphiphilic polyelectrolytes have already been studied. They increased the apparent water-solubility of hydrophobic compounds, but were toxic or not degradable, thus could not be eliminated from the body. In this work, we describe the synthesis of various substituted malolactones. Anionic ring opening copolymerization of these lactones yielded random amphiphilic polyanions with varying and controlled hydrophobization ratio and aliphatic and aromatic side chains with different lengths. These polymers increase the apparent water-solubility of hydrophobic compounds. A synergy between hydrophobic and electrostatic interactions has been demonstrated when the compound is cationic. The apparent solubility of anti-infectious drugs could thus be increased by several orders of magnitude. Under intravenous injection conditions (NaCl 9 g.L-1 and pH = 7,5), these polymers form preferentially intramolecular micelles, which are not sensitive to dilution effects. As a consequence, such a drug transport system would yield no premature release. Being also degradable, these polymers could release the drug and be eliminated from the body. They meet all main physico-chemical criteria to become a drug transport system.

The design of biomaterials, historically initiated and developed by physicians and engineers, in the last decades has slowly shifted toward a more biochemical based approach. For the replacement, repair and regeneration of tissues scientists are now focusing on materials that stimulate specific biological response at the molecular level. These biomaterials have already shown interesting applications in cell proliferation, differentiation, and extracellular matrix production and organization when the material modifications are designed to elicit specific interactions with cell integrins. In the present work we propose the application of this strategy for the development of blood-compatible materials. We first identified, in the coagulation cascade a key enzyme that constitute a valuable biological target for the development of anti-thrombogenic compounds. Piperazinyl-amide derivatives of N-alfa-(3-trifluoromethyl-benzenesulfonyl)-L-arginine were synthesized as graftable thrombin inhibitors. These inhibitors provided a spacer arm for surface grafting and a fluorine tag for XPS (X-ray photoelectron spectroscopy) detection. The possible disturbance of biological activity due to a variable spacer-arm fixed on the N-4 piperazinyl position was evaluated in vitro against human alfa-thrombin, in silico by molecular modelling and via X-ray diffraction study. Selected inhibitors, having inhibition potency in the mM range, were grafted on polyesters surface via wet chemistry and photochemical activation treatments. Wet chemistry surface grafting was performed by specific hydroxyl chain-ends activation and resulted in bioactive molecules fixation of 20-300pmol/cm2. The photochemical grafting was performed using a molecular clip providing an aromatic azide, for nitrene insertion into a polymer, and an activated ester for grafting of tag compounds. This grafting technique resulted in a dramatic increase in fixed bioactive signals (up to nmol/cm2). The material blood-compatibilization induced by the surface fixation of the inhibitors, was measured by a static blood clot weight measurement test. The wet chemistry grafting technique resulted in moderate blood-compatibilization while by the photochemical grafting method important decrease in surface blood clot formation was observed. In the latter case, the blood response to material contact was found to be strongly affected by the polyester surface photo-degradation induced by the activation treatment.

The design of biomaterials, historically initiated and developed by physicians and engineers, in the last decades has slowly shifted toward a more biochemical based approach. For the replacement, repair and regeneration of tissues scientists are now focusing on materials that stimulate specific biological response at the molecular level. These biomaterials have already shown interesting applications in cell proliferation, differentiation, and extracellular matrix production and organization when the material modifications are designed to elicit specific interactions with cell integrins. In the present work we propose the application of this strategy for the development of blood-compatible materials. We first identified, in the coagulation cascade a key enzyme that constitute a valuable biological target for the development of anti-thrombogenic compounds. Piperazinyl-amide derivatives of N-alfa-(3-trifluoromethyl-benzenesulfonyl)-L-arginine were synthesized as graftable thrombin inhibitors. These inhibitors provided a spacer arm for surface grafting and a fluorine tag for XPS (X-ray photoelectron spectroscopy) detection. The possible disturbance of biological activity due to a variable spacer-arm fixed on the N-4 piperazinyl position was evaluated in vitro against human alfa-thrombin, in silico by molecular modelling and via X-ray diffraction study. Selected inhibitors, having inhibition potency in the mM range, were grafted on polyesters surface via wet chemistry and photochemical activation treatments. Wet chemistry surface grafting was performed by specific hydroxyl chain-ends activation and resulted in bioactive molecules fixation of 20-300pmol/cm2. The photochemical grafting was performed using a molecular clip providing an aromatic azide, for nitrene insertion into a polymer, and an activated ester for grafting of tag compounds. This grafting technique resulted in a dramatic increase in fixed bioactive signals (up to nmol/cm2). The material blood-compatibilization induced by the surface fixation of the inhibitors, was measured by a static blood clot weight measurement test. The wet chemistry grafting technique resulted in moderate blood-compatibilization while by the photochemical grafting method important decrease in surface blood clot formation was observed. In the latter case, the blood response to material contact was found to be strongly affected by the polyester surface photo-degradation induced by the activation treatment.

Ces travaux menés à l’IMP@UJM ont pour objectifs la réalisation de films minces alimentaires 100% compostables par extrusion gonflage, thermoformage et biétirage. Des mélanges à base de farine plastifiée et de polyesters compostables ont été étudiés. La farine peut être déstructurée par extrusion bivis en présence de glycérol de manière similaire à l’amidon. La farine thermoplastique, ainsi obtenue, présente toutefois des différences notables avec l’amidon mais ne répond toujours pas aux applications visées. Son mélange avec des matrices polyester (PBAT et PLA) dans un procédé d’extrusion bivis a été réalisé et les morphologies caractérisées. La dispersion de la farine thermoplastique dans le PBAT, de type goutte / matrice, a été mise en étroite relation avec leur comportement rhéologique. Les propriétés mécaniques à l’état solide résultantes de ces mélanges ont été discutées en terme de microstructures, déformabilité de la phase dispersée et de l’adhésion à l’interface. Avec des charges modèles mélangées dans le PBAT et des analyses microscopiques sous déformation, le comportement mécanique de la phase dispersée a été clarifié. A l’état fondu, ces mélanges proposent des propriétés intéressantes mais limitées par les modifications de la matrice lors de son mélange avec la farine. Des défauts inhérents à la farine plastifiée et aux mélanges de polymères non compatibilisés ont été identifiés et une chimie adaptée a été développée. La polymérisation par ouverture de cycle du triméthylène carbonate à partir de fonctions hydroxyle en présence de catalyseurs organiques ou amorceurs organométalliques montre des cinétiques de réaction intéressantes pour un procédé d’extrusion réactive. Des fonctions hydroxyle modèle d’environnement chimique et stérique proche de l’amidon ont été utilisées pour l’amorçage de la polymérisation et les résultats ont été transposés aux fonctions hydroxyle de l’amidon, en présence ou non de glycérol. Une modification chimique de la farine thermoplastique, par greffage d’un polycarbonate, a donc été réalisée en extrusion réactive couplée au mélange avec le PBAT. Les effets compatibilisants ont ensuite été discutés en terme de microstructures, de réactions chimiques à l’interface farine plastifiée / PBAT et de modifications de la matrice PBAT. Les propriétés mécaniques de ces mélanges à l’état solide et fondu montrent des effets liés à la modification de l’interface / Thin compostable films for extrusion blowing, thermoforming and biaxial stretching are in the scope of these works. Blend of thermoplastic flour and compostable polyesters are proposed and studied. Corn flour can be processed in a twin-screw extruder with glycerol in a similar way than starch. Thermoplastic flour shows some differences with starch but still cannot be used in thin film applications. Thermoplastic flour was blended in a melt state with a compostable polyester matrix, PBAT. Matrix / particle morphologies were achieved and linked with individual rheological behaviour. Good global mechanical properties results from these morphologies were discussed in terms of microstructures, dispersed phase deformation under stress and interface properties. Model particles blends with PBAT and microscopical investigations confirmed the mechanical behavior of the dispersed phase. These blends still suffer from inherent problems concerning thermoplastic flour and uncompatibilized blends. A suitable chemistry was developed to overcome these defects based on monomer polymerization from starch. Ring opening polymerization of trimethylene carbonate in presence of hydroxyl functions and organic catalyst or organometallic initiators displays interesting reaction rates for a reactive extrusion process. Model co-initiators with chemical and sterical environments close to starch were used and transposed. Thermoplastic flour modification by polycarbonate grafting was achieved in a reactive extrusion process coupled with his blending in a melt state with PBAT matrix. Compatibilization effects were discussed in terms of microstructures, interface reactions and matrix modifications. Interface modifications were evidenced on mechanical properties of these blends

<p> </p><p>A chemoselective catalyst is preferred in a chemical reaction where protecting groups otherwise are needed. The two lipases <em>Candida antarctica </em>lipase B and <em>Rhizomucor miehei</em> lipase showed large chemoselectivity ratios, defined as (<em>k_cat</em>/<em>K</em>_M)_OH/ (<em>k_cat</em>/<em>K</em>_M)_SH, in a transacylation reaction with ethyl octanoate as acyl donor and hexanol or hexanethiol as acyl acceptor (<strong>paper I</strong>). The chemoselectivity ratio of the uncatalyzed reaction was 120 in favour of the alcohol. Compared to the uncatalyzed reaction, the chemoselectivity was 730 times higher for <em>Candida antarctica </em>lipase B and ten times higher for <em>Rhizomucor miehei</em> lipase. The <em>K</em>_M towards the thiol was more than two orders of magnitude higher than the <em>K</em>_M towards the corresponding alcohol. This was the dominating contribution to the high chemoselectivity displayed by the two lipases. In a novel approach, <em>Candida antarctica </em>lipase B was used as catalyst for enzymatic synthesis of thiol-functionalized polyesters in a one-pot reaction without using protecting groups (<strong>paper II</strong>). Poly(e-caprolactone) with a free thiol at one of the ends was synthesized in an enzymatic ring-opening polymerization initiated with mercaptoethanol or terminated with either 3-mercaptopropionic acid or g-thiobutyrolactone.</p><p> </p>

La préparation de polymères à base d’acides biliaires, molécules biologiques, a attiré l'attention des chercheurs en raison des applications potentielles dans les domaines biomédicaux et pharmaceutiques. L’objectif de ce travail est de synthétiser de nouveaux biopolymères dont la chaîne principale est constituée d’unités d’acides biliaires. La polymérisation par étapes a été adoptée dans ce projet afin de préparer les deux principales classes de polymères utilisés en fibres textiles: les polyamides et les polyesters. Des monomères hétéro-fonctionnels à base d’acides biliaires ont été synthétisés et utilisés afin de surmonter le déséquilibre stoechiométrique lors de la polymérisation par étapes. Le dérivé de l’acide lithocholique modifié par une fonction amine et un groupement carboxylique protégé a été polymérisé en masse à températures élevées. Les polyamides obtenus sont très peu solubles dans les solvants organiques. Des polyamides et des polyesters solubles en milieu organique ont pu être obtenus dans des conditions modérées en utilisant l’acide cholique modifié par des groupements azide et alcyne. La polymérisation a été réalisée par cycloaddition azoture-alcyne catalysée par l'intermédiaire du cuivre(Ι) avec deux systèmes catalytiques différents, le bromure de cuivre(I) et le sulfate de cuivre(II). Seul le bromure de cuivre(Ι) s’est avéré être un catalyseur efficace pour le système, permettant la préparation des polymères avec un degré de polymérisation égale à 50 et une distribution monomodale de masse moléculaire (PDI ˂ 1.7). Les polymères synthétisés à base d'acide cholique sont thermiquement stables (307 °C ≤ Td ≤ 372 °C) avec des températures de transition vitreuse élevées (137 °C ≤ Tg ≤ 167 °C) et modules de Young au-dessus de 280 MPa, dépendamment de la nature chimique du lien. / Bile acids have drawn attention in the synthesis of polymers for biomedical and pharmaceutical applications due to their natural origin. The objective of this work is to synthesize main-chain bile acid-based polymers. The step-growth polymerization was used to prepare two important classes of polymers used in textile fibers, polyamides and polyesters. Heterofunctional bile acid-based monomers were synthesized and used in order to overcome stoichiometric imbalances during step-growth polymerization. The lithocholic acid derivative bearing amine and protected carboxylic functional groups was polymerized in bulk at high temperatures, yielding polyamides that were poorly soluble in common organic solvents. Soluble triazole-linked polyamides and polyesters were obtained when the cholic acid derivative bearing azide and alkyne functional groups was polymerized under mild conditions via copper(Ι)-catalyzed azide-alkyne cycloaddition. Two different catalytic systems, copper(Ι) bromide and copper(ΙΙ) sulfate, were tested. Only copper(Ι) bromide proved to be an effective catalyst for the system, allowing the synthesis of the polymers with a degree of polymerization of ca. 50 and an unimodal molecular weight distribution(PDI ˂ 1.7). The main-chain cholic acid-based polymers are thermally stable (307 °C ≤ Td ≤ 372 °C) with high glass transition temperatures (137 °C ≤ Tg ≤ 167 °C) and Young’s moduli in excess of 280 MPa, depending on the chemical structure of the linker.

CHARLES UNIVERSITY IN PRAGUE Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical technology Name of the student: Klára Bílková Title of diploma thesis: Influence of plastification on rheological properties of oligoester of lactic acid and glycolic acid branched with dipentaerythritole Consultant: PharmDr. Eva Šnejdrová, Ph.D. The aim of this diploma thesis was the study of rheological properties of the oligoester of DL-lactic and glycolic acids branched with 1% of dipenthaerythritol (1D) and plasticized with 6 various plasticizers in increasing concentrations. Theoretical part was devoted to fundamentals of rheology and measurements of viscosity using rotational viscometers. It describes basic types and constructions of rotational rheometers and summarizes basic facts about bioadhesion and use of rheological method for assessment of bioadhesion. There were prepared matrices from oligoester 1D and plasticizers in concentrations of 20 %, 30 % and 40 % in the experimental part. These plasticizers were tested: ethyl pyruvate, ethyl salicylate, methyl salicylate, triacetin, tributyrin and triethyl citrate. Rheological properties were examinated at 37 řC using spindle viscometer and at 37 řC and 50 řC using rotational rheometer. Rheograms were used to characterize flow properties of tested...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Student: Lenka Šišáková Supervisor of Diploma thesis: PharmDr. Eva Šnejdrová, Ph.D. Title of Diploma thesis: Aciclovir release from mucoadhesive matrices The aim of this diploma thesis was the study of the mucoadhesive parameters of plasticized oligoester of lactic acid and glycolic acid and 3% mannitol as a branching monomer. Knowledge of dissolution testing of drug release from dosage form, principal theories and mechanisms of mucoadhesion and mucoadhesion testing of adhesive formulation is described in theoretical part. Matrices formed from terpolymer of D,L-lactic acid, glycolic acid branched with mannitol and 5 % aciclovir were examined in the experimental part. Triethylcitrate (TEC), ethylpyruvate (EP), methylsalicylate (MS) and ethylsalicylate (ES) were used as plasticizers. Dissolution test has been done. Hydrated mucin from porcine stomach was used as a base. Phosphate-citrate buffer pH 7.4 was used as a dissolution medium. Dissolution was defined as a quantity of released aciclovir in to the dissolution medium after 15, 30, 60 and 90 minutes. The quantity of the released aciclovir was defined by a spectrophotometry. In 90 minutes was released 43 % of aciclovir from the matrice...